Lesioned spinal cord long-tract axons can grow into a lesion/graft site if growth factors are locally provided. Separately, intraganglionic elevation of cAMP can promote dorsal column sensory sprouting after spinal cord lesions. However, achieving host axonal growth beyond cell grafts placed in spinal cord lesion sites has proven difficult, yet will likely be required for functionally meaningful recovery after SCI. Recently, we succeeded in promoting axonal regeneration into and beyond sites of cervical SCI using a combinatorial approach of: 1) cAMP stimulation of the neuronal soma, 2) autologous cell bridges in the lesion site, and 3) growth factor gradients provided as stimuli to axons in and beyond the lesion site. Controls lacking all three of these treatments did not exhibit bridging. This project will further develop this approach, identify its mechanistic underpinnings, and reduce it to potential clinical practicality. The following specific aims will be pursued: Specific Aim 1: Determine whether a combinatorial approach to regeneration will promote axonal regeneration and functional recovery after spinal cord lesions. Specific Aim 2: Determine whether a combinatorial approach to regeneration will promote tissue sparing, axonal regeneration and functional recovery after acute spinal cord contusions. Specific Aim 3: Determine whether a combinatorial approach to regeneration will promote axonal regeneration and functional improvement after chronic spinal cord contusions. The UCSD Center for Neural Repair also has in place primate SCI models for proof-of-concept testing of these findings, allowing potential reduction to practicality. We further have a track record of responsibly translating promising therapies from the bench to bedside.